Multiple Myeloma
Multiple Myeloma (myeloma) is a bone-marrow malignancy of plasma cells. Collections of abnormal plasma cells accumulate in the bone marrow, where they interfere with the production of normal blood cells. Myeloma is the second most common hematological malignancy in the U.S. (after non-Hodgkin lymphoma), and constitutes 13% of haematologic malignancies and 1% of all cancers. The disease is burdensome in terms of suffering as well as medical expenditure since it causes pathological fractures, susceptibility to infection, renal and then bone-marrow failure before death.
Unlike many lymphomas, myeloma is currently incurable. Standard chemotherapy agents used in lymphoma are largely ineffective for myeloma. In addition, since CD20 expression is lost in plasma cells, Rituximab cannot be used against this disease. New agents such as Bortezamib and Lenolidomide are partially effective, but fail to lead to long-lasting remissions.
There is thus a need for alternative agents for the treatment of myeloma which have increased efficacy and improved long-term effects.
BCMA
BCMA, also known as TNFRSF17, is a plasma cell specific surface antigen which is expressed exclusively on B-lineage haemopoietic cells or dendritic cells. It is a member of the TNF receptor family. BCMA is not expressed on naïve B cells but is up-regulated during B-cell differentiation into plasmablasts, and is brightly expressed on memory B cells, plasmablasts and bone marrow plasma cells. BCMA is also expressed on the majority of primary myeloma cells. Apart from low levels of mRNA detected on dendritic cells, BCMA expression appears to be absent on other tissues, indicating the potential as a target for novel therapeutics for multiple myeloma.
BCMA functions within a network of interconnected ligands and receptors which is shown schematically in FIG. 1. Two other TNF receptors share the ligands APRIL and BAFF with BCMA—transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI, also known as TNFRSF13B), which is found on activated T-cells and all B-cells; and BAFF-R (TNFRSF13C) which is predominantly expressed on B-lymphocytes. Multiple myeloma cells express TACI in some cases and BCMA in most cases, but never BAFF-R.
The natural ligand APRIL is potentially useful as or as part of a BCMA-targeting therapeutic. However, cross-reaction with TACI is potentially a problem, because TACI is found on activated T-cells and all B-cells, so treatment with an agent directed to BCMA on myeloma cells may also cause a pathological depletion of non-cancerous B and T cell subsets.
APRIL is also potentially useful in diagnostic applications to identify plasma cells, in particular the presence of malignant plasma cells in conditions such as multiple myeloma. However, again, the capacity of APRIL to also bind TACI means that APRII-based diagnostics will also identify generally activated T-cells and all B-cells, meaning that the results are ambiguous.
There is thus a need to develop anti-BCMA therapeutics and diagnostics which are not associated with these disadvantages.